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PubMed1988

Development and growth of palatal rugae in the mouse.

Palatal rugae began to develop in the mouse, before the elevation of the palatal shelves, as localized regions of epithelial proliferation and thickening. Subsequently, fibroblasts and collagen fibres accumulated in the connective tissue subjacent to the thickened epithelium and later assumed a distinctive orientation, the fibres running anteroposteriorly within the core and in concentric curves across the base of each ruga. The role of collagen in rugal morphogenesis was examined after inhibiting its formation by feeding the lathyritic agent beta-aminopropionitrile to pregnant females. This substance markedly affected the eventual height of the rugae at birth, confirming the importance of collagen in rugal development.

Animals↗
PubMed2002

Low density lipoproteins downregulate lysyl oxidase in vascular endothelial cells and the arterial wall.

OBJECTIVE: Hypercholesterolemia induces endothelial dysfunction, a hallmark of the atherosclerotic process, modulating the expression of key genes in vascular endothelial cells. METHODS AND RESULTS: By differential display analysis, we have studied the effect of high concentrations of native low density lipoprotein (LDL) on endothelial gene expression. mRNA levels of lysyl oxidase (LOX), an enzyme involved in collagen and elastin cross-linking, were downregulated by LDL treatment in endothelial cells in a dose- and time-dependent manner (80% of inhibition by 180 mg/dL LDL for 24 hours). This reduction of LOX expression was associated with a decrease in LOX activity (40% and 54% of inhibition after 24 and 48 hours of LDL treatment, respectively). LOX mRNA half-life was not modified by LDL, but transcriptional inhibition blocked the effect of LDL. Inhibition of LOX activity by either LDL or beta-aminopropionitrile, an inhibitor of LOX, increased endothelial permeability (192+/-0.19- and 3.37+/-0.74-fold, respectively). Interestingly, a reduction in LOX expression (3.5-fold) was observed in vivo in the vascular wall of hypercholesterolemic pigs. CONCLUSIONS: These findings suggest that LDL downregulation of LOX could contribute to the endothelial dysfunction caused by hypercholesterolemia, thus contributing to atherosclerotic plaque formation.

Animals↗
PubMed1990

Elastic skeleton of intracranial cerebral aneurysms in rats.

In an attempt to clarify the developmental mechanism of cerebral aneurysms, we studied the elastic skeleton of experimentally induced cerebral aneurysms in rats under scanning electron microscopy after hot formic acid extraction followed by freeze-drying. We produced cerebral aneurysms in 19 rats by unilaterally ligating the common carotid artery, inducing renal hypertension, and feeding beta-aminopropionitrile fumarate. The first noted change was the loss of folds protruding from the internal elastic lamina. Morphologic changes of the internal elastic lamina, considered to be primarily responsible for aneurysmal formation, occurred after the loss or disintegration of the elastic skeleton of first the intima, then the media. In large aneurysms with thick domes, we found proliferation of elastic lamellae that may reduce the risk of rupture. It seems probable that the complex elastic skeleton of the arterial wall may account for the mechanical properties of the artery and that growth of an aneurysm occurs due to disintegration of the elastic skeleton and not simply to rupture of the internal elastic lamina. We believe that such changes in the elastic skeleton are a property of the functional state of the cells that produce elastin.

Animals↗
PubMed1979

Scleroderma: increased biosynthesis of triple-helical type I and type III procollagens associated with unaltered expression of collagenase by skin fibroblasts in culture.

To assess potential abnormalities in collagen metabolism in systemic scleroderma, skin fibroblast lines from patients with this disease were established and compared to control cell lines derived from healthy subjects. For studies on the biosynthesis of procollagen, the cells were incubated with [(14)C]proline in a medium supplemented with ascorbic acid and beta-aminopropionitrile, and the synthesis of nondialyzable [(14)C]hydroxyproline, in relation to DNA or cell protein, was taken as an index of procollagen formation. Five of eight scleroderma fibroblast cell lines demonstrated procollagen biosynthesis rates significantly higher than the controls, and the mean rate of procollagen synthesis by scleroderma fibroblasts was about twice that of the control cells. Control experiments demonstrated that the specific activity of the intracellular free proline was not different in scleroderma and control fibroblasts, and the mean population doubling times of the scleroderma and the control fibroblast cell lines were the same. The relative synthesis of the genetically distinct procollagens was examined by isolating type I and type III procollagens from the cell culture medium using DEAE-cellulose chromatography. The ratios of type I/III procollagens in scleroderma cell lines did not differ from the controls. The helical stability of the collagenous portion of type I and type III procollagens, estimated by the resistance of (14)C-collagen to limited proteolytic digestion with pepsin under nondenaturing conditions, was the same in both scleroderma and control cultures. The capacity of the cells to synthesize enzymatically active and immunologically reacting collagenase was also studied; no marked differences in these parameters could be observed. The results suggest that cultured skin fibroblasts from patients with scleroderma demonstrate a metabolic abnormality expressed as increased synthesis of type I and type III procollagens in a normal ratio. This abnormality may play a role in the excessive accumulation of collagen in the skin and other organs affected in scleroderma.

Adolescent↗
PubMed1998

Comparison of elastolytic activity between experimental aneurysm and experimental diabetes mellitus.

In order to clarify the degradation of elastin under abnormal conditions, we examined the aortic elastolytic activity in rat experimental diabetes mellitus induced by treatment with streptozotocin and in rat experimental aneurysm induced by treatment with an inhibitor of lysyloxidase (beta-aminopropionitrile: BAPN). Measurement of the aortic elastolytic activity used 14C-labeled elastin as the substrate, and the determined value was compared with the aortic lysosomal enzyme (acid phosphatase) activity. In the case of experimental diabetes, the aortic elastolytic activity was not changed, but the aortic acid phosphatase activity was significantly increased compared with the control. In the case of the experimental aneurysm, the aortic elastolytic activity measured after 2 and 3 weeks was increased compared with each control. There was a negative correlation (r=-0.435, n=36) between the elastolytic activity and the cross-linking (desmosine) content in the aorta. The ratio of elastolytic activity to desmosine content was significantly increased compared with the control. Therefore, the degradation of aortic elastin in the experimental aneurysm was caused by elastase, not by lysosomal enzymes. We concluded that an elastase-like enzyme mainly contributed to the degradation of elastin in the experimental aneurysm since the inhibitory pattern of the elastolytic activity in the experimental aneurysm was similar to that of pancreatic elastase.

Animals↗
PubMed1980

Biosynthesis of tropoelastin by elastic cartilage.

Elastic ear cartilage and aortae from nine-day-old hamsters were incubated in Krebs-Ringer medium containing ascorbate, beta-aminopropionitrile and either [14C]proline or [3H]valine. The [14C]proline-labeled proteins were separated by chromatography on Agarose A-5 m in sodium dodecyl sulfate and their [14C]-hydroxyproline content measured. A fraction having an approximate molecular weight of 70,000 measured by polyacrylamide gel electrophoresis had a [14C]hydroxyproline content of 9.1% in the cartilage and 11.8% in the aorta. This fraction was also relatively heavily labeled with [3H]valine. The 70,000 dalton, [3H]valine-labeled protein of both the aorta and ear cartilage was precipitated by elastin-specific antibody prepared against hamster insoluble aorta elastin, but no higher molecular weight protein was immunoprecipitated. Based on these results we identify the 70,000 dalton protein from the elastic cartilage as tropoelastin.

Animals↗
PubMed1981

Identification of elastin in developing aortic tissue by immunological methods.

Antibodies raised in rabbits to tropoelastin isolated from lathyritic chick aorta were conjugated with ferritin and used to identify and locate elastin-containing elements in sections of aortic tissue from developing chicks. The ferritin-antibody conjugate was associated with a network of fine filaments with a diameter of 3-5 nm which, in the 8-10 day old chick embryo aorta, was distributed between and around small but recognizable elastic fibers. In older aortic tissue this ferritin-labelled material was seen principally in loose association with the periphery of developing elastic fibers. The microfibrils did not interact with the ferritin-antibody conjugate. Treatment of chicks with beta aminopropionitrile did not interfere with the accumulation of ferritin-labelled filaments on these small elastic fibers, suggesting that the mechanism of addition of new material onto growing fibers may be independent of cross-linking.

Amino Acids↗
PubMed1986

Comparison of lysyl oxidase from bovine lung and aorta.

A prior report had concluded that bovine lung lysyl oxidase displayed an unusual resistance to inhibition by beta-aminopropionitrile (BAPN) in contrast to the enzyme isolated from other connective tissues. Therefore, lysyl oxidase was purified from fetal bovine lung and from aorta of young calves by parallel procedures, and key chromatographic and catalytic properties of these enzymes were directly compared. The enzymes prepared from both tissues each demonstrated the same multiplicity of enzyme species which resolve on DEAE-cellulose and otherwise demonstrated the same chromatographic behavior on gel exclusion media and on collagen-Sepharose and Cibacron blue-Sepharose columns. The activities of the unresolved but partially purified enzyme species of lung and of aortic lysyl oxidase were each fully inhibitable by approximately the same low (mu molar) concentrations of BAPN. Thus, the enzymes of both tissues were found to be very similar to each other by several criteria.

Amino Acid Oxidoreductases↗
PubMed1996

Collagen and proteoglycan production by bovine fetal and adult chondrocytes under low levels of calcium and zinc ions.

The experiments described herein tested the effects of CaCl2 and ZnCl2, added at various concentrations in the culture medium, upon the synthesis of collagen and proteoglycan by adult and fetal (articular, epiphyseal and hypertrophic) bovine chondrocytes maintained in high density multilayer cultures. CaCl2 concentrations below 0.5 mM or the addition of 1-50 microM ZnCl2 to the medium selectively promoted the production of collagen by all four populations of chondrocytes but had no effect on fibroblasts. Further, these changes had no statistically significant effect on the incorporation of 35S-sulfate into macromolecules or on the synthesis of gelatinase A, measured by gelatin zymography. The addition of CaCl2 and ZnCl2 at these concentrations did not result in a change in the relative proportion of non-crosslinked 3H-collagen molecules (synthesized in the presence of beta-aminopropionitrile) partitioning in the cell layer and medium compartments, and did not appreciably alter the pattern of collagens synthesized by any of the cell populations. The hypertrophic cells synthesized high levels of collagen type X in the presence as well as absence of exogenously added cations. However, CaCl2 at 10 mM caused a marked upregulation of collagen type X synthesis by a preparation of chondrocytes derived from the entire growth plate, consistent with the view that calcium at that concentration stimulated the differentiation of some of the cells into hypertrophic chondrocytes.

Animals↗
PubMed1999

Proteins secreted by vascular smooth muscle cells as substrates of lysyl oxidase.

The mixture of proteins secreted by neonatal rat aorta smooth muscle cells cultured in the presence of beta-aminopropionitrile was readily oxidized and polymerized upon incubation with purified or crude preparations of lysyl oxidase. Western blot analysis indicated that these substrates included 30-60kDa protein bands reactive with anti-elastin, presumed to be fragments derived from tropoelastin. Thus, truncated, elastin-like as well as other proteins accumulate in the media of these cultures which, in toto, can serve as a conveniently prepared, highly efficient substrate for the routine assay of lysyl oxidase activity.

Animals↗
PubMed1991

Cerebral blood flow patterns at major vessel bifurcations and aneurysms in rats.

Cerebral arterial bifurcations in rats were treated to induce cerebral aneurysms experimentally, and flow patterns of latex particles introduced under a constant flow rate were analyzed with a 16-mm cine-camera and videocassette recorder. Cerebral aneurysms were produced by ligating one common carotid artery, inducing experimental hypertension, and feeding the animals beta-aminopropionitrile. After perfusion and fixation, samples of cerebral arterial bifurcations with shallow invaginations and with small aneurysms were obtained and used for analysis. Bifurcations in rats without experimental treatment were used as control specimens. Flow studies in the control bifurcations showed that the apical intimal pad, not the apex itself, acted as the flow divider. Small particles tended to accumulate at the region just distal to the apical intimal pad, where the initial aneurysmal changes are known to occur. This indicates stagnation of flow at that site. In the bifurcations with shallow invaginations and small aneurysms, a marked pressure gradient was present at the proximal end of the aneurysm orifice. A tendency for stagnation of small particles near the aneurysm wall was also observed. The wall shear stress was highest at the distal end of the aneurysmal orifice, which may be responsible for the development of these lesions.

Animals↗
PubMed2005

Collagen production in cardiac fibroblasts during inhibition of aminopeptidase B.

OBJECTIVE: To determine whether the aminopeptidase B inhibitor, arphamenine A, could affect collagen production and expression in control and TGF-ss1-treated cardiac fibroblasts. DESIGN AND METHODS: Cardiac fibroblasts from passage 2 from normal male adult rats were cultured to confluency and incubated with and without 600 pmol/l TGF-ss1 for 2 days in serum-free Dulbecco's modified Eagle's medium and then incubated with 100 mol/l arphamenine A for 1 day in this medium with added ascorbic acid, ss-aminopropionitrile and titriated proline. Soluble collagen was measured in the conditioned medium and non-soluble collagen in the cell layer. Aminopeptidase activity was estimated by spectrophotometric determination of the liberation of p-nitroaniline from alanine- or arginine-p-nitroanilide. Matrix metalloproteinase (MMP) and lysyl oxidase activity were assayed in the conditioned medium. A semi-quantitative reverse transcriptase- polymerase chain reaction was used to examine the expression of lysyl oxidase and collagen type I and III. RESULTS: Arphamenine A dose-dependently inhibited basal and TGF-ss1-stimulated aminopeptidase activity. Arphamenine A reduced soluble and non-soluble collagen production in control and TGF-ss1-treated cardiac fibroblasts, while it decreased collagen type I and III expression only in TGF-ss1-treated fibroblasts. Lysyl oxidase, MMP-1 and MMP-2 activity were inhibited by arphamenine A in the conditioned media of control and TGF-ss1-treated cardiac fibroblasts. CONCLUSIONS: Our data show that the specific aminopeptidase B inhibitor, arphamenine A, reduces collagen production in cardiac fibroblasts and that this reduction is accompanied by a pronounced inhibition of lysyl oxidase.

Alanine↗
PubMed1998

[Effects of an extract of salviae miltiorrhizae (764-3) on structural remodeling of intra-acinar pulmonary artery in pulmonary hypertension due to chronic hypoxia and monocrotaline in rats].

OBJECTIVE: To investigate the effects of an extract of salviae miltiorrhizae (764-3) on the percentage of intra-acinar muscular artery (MA), partal MA(PMA) and nonmuscular MA(NMA) and collagen deposition in the media of MA in rats with hypoxia and MCT-induced pulmonary hypertension. METHOD: Wistar rats were divided into 12 groups. The hypobaric hypoxic 51 kPa (1 kPa = 7.5 mmHg) and MCT (60 mg/kg intraperitoneal injection) rats were treated with 764-3 (20 mg/kg), beta-aminopropionitrile (BAPN, 150 mg/kg) and 764-3 (40 mg/kg), respectively. At each time point, the hemodynamic and morphological parameters were measured. RESULT: After hypoxia for 2 weeks, the percentage of MA increased (P < 0.001), of NMA decreased (P < 0.001) and of PMA no obvious change; and after 4 weeks, the above changes became to be more striking and the collagen content in the media of MA increased (P < 0.001). The MCT-treated rats had more severe changes than the hypoxic rats. Both 764-3 and BAPN could inhibit the changes, decreased the collagen content and BAPN was more effective than 764-3(P < 0.05). CONCLUSION: 764-3 can partially inhibit collagen deposition in pulmonary arterioles attenuate hypoxia and MCT-induced pulmonary hypertension, reduce the percentage of MA, and has a moderate influence on collagen deposition as compared with BAPN.

Animals↗
PubMed1992

Characterization of an associated microfibril protein through recombinant DNA techniques.

The complete primary structure of a new extracellular protein associated with elastic fiber microfibrils was determined by recombinant DNA techniques. Antiserum to insoluble bovine ocular zonule protein was used to screen a lambda gt11 cDNA expression library constructed from whole chick embryo poly(A)+ RNA. The cDNAs encoding immunoreactive fusion polypeptides were then used to rescreen the library by plaque hybridization. Nucleotide sequencing of overlapping cDNA clones revealed an open translation reading frame of 1326 bases beginning at an initiation start sequence and ending at a stop codon. The contiguous cDNA sequence contains a 3'-untranslated region of 563 bases with a possible polyadenylation site 16 bases upstream from the poly(A) tail. Primer extension of chick aortic mRNA taken together with the sequence data, reveals a 5'-untranslated region of 95 bases extending upstream from the translation start site. Northern blot analyses indicated that the isolated cDNA hybridized with a 2.1-kilobase mRNA in preparations of whole chick embryo and chick embryonic aortic, heart, and muscle RNAs. The initial translation protein encoded by the cDNA is 53,932 kDa and possesses a hydrophilic amino acid composition with glutamic acid comprising 22% of the total amino acid residues. Antiserum was elicited to a synthetic peptide sequence (14 amino acids) encoded within the deduced protein primary structure. Western blots of extracted proteins from chick embryonic aortae cultured in the presence of beta-aminopropionitrile showed that the medium and a mild salt extract contained an immunoreactive protein possessing an apparent molecular mass of 58,000 whereas harsh denaturants extracted a 32,000-kDa protein. Pulse-chase experiments using radiolabeled lysine showed that the newly synthesized 58,000-kDa protein was chased into a 32,000-kDa protein within a 2-24-h period. Immunoelectron microscopy of tissue sections from chick aortae, bovine nuchal ligament, and human ocular zonules showed that the peptide-elicited antibody localized specifically to ultrastructurally definable microfibril structures.

Amino Acid Sequence↗
PubMed1992

Type I collagen fibril formation by human vascular endothelial cells in culture.

The formation of type I collagen fibrils by vascular human endothelial cells in culture was demonstrated by the indirect immunofluorescence method. The fibrillar structure was formed on the cell surface on the third day after subcultivation and had grown like a knitting ball of 0-3 microns in diameter and 0-200 microns in length on the seventh day. The fibril formation was stimulated by the addition of basic fibroblast growth factor, but completely blocked by the presence of beta-aminopropionitrile. The fibrils were eliminated by the treatment with clostridial collagenase or with 0.5% Triton X-100. The pathophysiological significance of type I collagen fibril formation by vascular endothelial cells in vascular diseases is also discussed.

Cells, Cultured↗
PubMed1976

Demonstration of a precursor-product relationship between soluble and cross-linked elastin, and the biosynthesis of the desmosines in vitro.

Direct evidence showing that a soluble form of elastin is the precursor of cross-linked elastin was obtained from pulse-chase experiments using chick embryo aortas and by demonstrating the conversion of soluble elastin into cross-linked elastin in a cell-free system. Acetic acid extracts of embryonic chick aorta pulse-labeled with [14C]lysine contain two radioactive proteins of molecular weights 74,000 and 138,000 which have been identified previously as soluble elastin and the pro-alpha chain of collagen, respectively. In pulse-chase experiments, the radioactivity incorporated in the soluble elastin during the pulse with [14C]lysine disappeared during a 24-hour chase with [12C]lysine and 89% of that which disappeared was accounted for in the desmosines of alkali-insoluble elastin. The disappearance of the radioactivity from the soluble fraction and its appearance in the desmosines of elastin were inhibited by beta-aminopropionitrile, a specific inhibitor of the cross-linking enzyme lysyl oxidase. In addition in vitro experiments, it was shown that the radioactivity in the desmosines of elastin can arise from that present in an acid-soluble precursor protein. This precursor protein is soluble elastin, as demonstrated by the formation of desmosines when a homogeneous preparation of soluble elastin was incubated with purified lysyl oxidase.

Amino Acids↗
PubMed1987

Experimental systems which modify and simulate rapeseed-induced liver haemorrhages in in-lay hens.

The occurrence of liver haemorrhages was compared when diets containing 30 or 40 per cent rapeseed meal (RSM) or 30 per cent soybean meal (SBM), with and without experimental additives, were fed to in-lay hens of a commercial egg-producing strain for 12 weeks. The incidence of haemorrhages was significantly greater when the birds were maintained on the basal (unsupplemented) RSM diet than on the equivalent SBM diet. Haemorrhages were either small and infrequent, minute and multiple as in peliosis hepatis, or large enough to rupture the liver capsule. They might be recent or old and encapsulated, sometimes both varieties affecting the same specimen, and they occurred in any part of the liver. Histologically, hepatocyte necrosis and reticulin derangement were not detected in livers without gross haemorrhages and even in those with haemorrhages these abnormalities were only seen closely adjacent to haemorrhages or to foci of eosinophilic fibrinoid. In some instances there was sinusoidal ectasia. Separate additions of 50 g dried skimmed milk powder, 0.5 g zinc oxide, 0.25 g ferrous sulphate or 2.0 mg selenium (as sodium selenite) kg-1 to the basal RSM diet did not significantly modify the incidence of haemorrhage. Ferrous sulphate slightly reduced goitrogenicity. Supplements of 2.2 mg menadione and 1.0 g sodium phenobarbital kg-1 RSM diet induced slight reductions in the number of cases of liver haemorrhage or their severity, indicating that the multifunction oxidase system may be involved in rapeseed hepatotoxicity. The addition of 0.5 g methimazole kg-1 to the basal SBM diet induced severe colloid goitre but did not induce liver haemorrhage. Both thiouracil (0.5 g kg-1 diet) and beta-aminopropionitrile (0.5 g and 2.5 g kg-1 diet) when added to the basal SBM diet induced liver haemorrhages which did not differ in incidence or histological appearance from those induced by RSM. Hyperplastic goitre was caused by thiouracil. Intrahepatic cholestasis induced by sodium taurolithocholate, bilirubin and alpha-naphthylisothiocyanate and extrahepatic cholestasis induced by bile duct ligation resulted in hepatocyte necrosis but not gross liver haemorrhages. Spontaneous deaths due to conditions other than liver haemorrhages were significantly more numerous in RSM-fed than SBM-fed hens.(ABSTRACT TRUNCATED AT 400 WORDS)

Animal Feed↗